Decreased calcineurin and increased phosphothreonine‐DARPP‐32 in the striatum of rats behaviorally sensitized to methamphetamine

Lin, Xian-Hao; Hashimoto, Takeshi; Kitamura, Noboru; Murakami, Naoya; Sato, Osamu; Maeda, Kiyoshi

doi:10.1002/syn.10071

Cited by 18 publications

(17 citation statements)

References 35 publications

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“…In NAc however, chronic cocaine stimulated DARPP-32 expression. In agreement with previous studies (Lin et al, 2002;Hu et al, 2005), chronic cocaine administration increased DARPP-32 expression in NAc (po0.001), but not in the dorsal striatum. DARPP-32 upregulation was not observed when GS39783 was applied 30 min before each daily cocaine administration (po0.001).…”

Section: Gs39783 Blocks Chronic Cocaine-induced Upregulation and Actisupporting

confidence: 93%

GABAB Receptor-Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

Lhuillier

Mombereau

Cryan

et al. 2006

Neuropsychopharmacol

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Exposure to cocaine induces selective behavioral and molecular adaptations. In rodents, acute cocaine induces increased locomotor activity, whereas prolonged drug exposure results in behavioral locomotor sensitization, which is thought to be a consequence of druginduced neuroadaptive changes. Recent attention has been given to compounds activating GABA B receptors as potential antiaddictive therapies. In particular, the principle of allosteric positive GABA B receptor modulators is very promising in this respect, as positive modulators lack the sedative and muscle relaxant properties of full GABA B receptor agonists such as baclofen. Here, we investigated the effects of systemic application of the GABA B receptor-positive modulator GS39783 (N,N 0 -dicyclopentyl-2-methylsulfanyl-5-nitropyrimidine-4, 6-diamine) in animals treated with acute and chronic cocaine administration. Both GS39783 and baclofen dose dependently attenuated acute cocaine-induced hyperlocomotion. Furthermore, both compounds also efficiently blocked cocaine-induced Fos induction in the striatal complex. In chronic studies, GS39783 induced a modest attenuation of cocaine-induced locomotor sensitization. Chronic cocaine induces the accumulation of the transcription factor DFosB and upregulates cAMP-response-element-binding protein (CREB) and dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). GS39783 blocked the induction/activation of DARPP-32 and CREB in the nucleus accumbens and dorsal striatum and partially inhibited DFosB accumulation in the dorsal striatum. In summary, our data provide evidence that GS39783 attenuates the acute behavioral effects of cocaine exposure in rodents and in addition prevents the induction of selective long-term adaptive changes in dopaminergic signaling pathways. Further investigation of GABA B receptor-positive modulation as a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse is therefore warranted.

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Section: Gs39783 Blocks Chronic Cocaine-induced Upregulation and Actisupporting

confidence: 93%

GABAB Receptor-Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

Lhuillier

Mombereau

Cryan

et al. 2006

Neuropsychopharmacol

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“…The observed increase in the levels of DARPP-32 within the COC-withdrawn NAc is similar to that found in behaviorally sensitized rats after repeated treatment with methamphetamine (Lin et al, 2002). These findings suggest a possible common mechanism underlying the increase of DARPP-32 following chronic exposure to psychostimulants.…”

Section: Phosphorylation Of Na þ Channels Was Increased In Coc-withdrsupporting

confidence: 80%

“…Besides the increased PKA activity and attenuated Ca 2þ signaling after chronic COC treatment (Terwilliger et al, 1991;Zhang et al, 2002;Hu et al, 2004), the protein levels of DARPP-32 and CaN are also increased and decreased, respectively, after repeated administration of methamphetamine (Lin et al, 2002). Although these changes in PKA activity and Ca 2þ signaling appear to be associated with decreased I Na found in COCwithdrawn NAc neurons, whether and how CaN-and PKAactivated p-Thr.34-DARPP-32 are functionally involved in chronic COC-induced I Na reduction requires determination.…”

Section: Introductionmentioning

confidence: 99%

Repeated Cocaine Administration Decreases Calcineurin (PP2B) but Enhances DARPP-32 Modulation of Sodium Currents in Rat Nucleus Accumbens Neurons

Ford

White

2005

Neuropsychopharmacol

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Our previous studies have demonstrated that repeated cocaine (COC) administration reduces voltage-sensitive sodium and calcium currents (I Na or VSSCs and I Ca or VSCCs, respectively) in medium spiny nucleus accumbens (NAc) neurons of rats. The present findings further indicate that chronic COC-induced I Na reduction in NAc neurons is regulated by decreased dephosphorylation and enhanced phosphorylation of Na þ channels. Whole-cell voltage-clamp recordings revealed that dephosphorylation of Na þ channels by calcineurin (CaN) enhanced I Na , while inhibition of protein phosphatase 1 (PP1) by phosphorylated dopamine-and cAMP-regulated phosphoprotein (M r ¼ 32 kDa) (DARPP-32) at the site of threonine 34 (p-Thr.34-DARPP-32) suppressed I Na , in freshly dissociated NAc neurons of saline-pretreated rats. However, the effects of CaN on enhancing I Na were significantly attenuated, and the action of p-Thr.34-DARPP-32 to decrease I Na was mimicked, although not potentiated, by repeated COC pretreatment. Dephosphorylation of Na þ channels by PP1 also enhanced I Na , but this effect of PP1 on I Na was not apparently affected by repeated COC administration.Western blot analysis indicates that the protein levels of CaN and DARPP-32 were significantly decreased and increased, respectively, while the PP1 levels were unchanged, in the COC-withdrawn NAc as compared to saline-pretreated controls. Combined with previous findings, our results indicate that both CaN and PP1 modulate the increase in I Na via enhancing dephosphorylation, while p-Thr.34-DARPP-32 reduces I Na by inhibiting PP1-induced dephosphorylation, thereby stabilizing the phosphorylation state, of Na þ channels in NAc neurons. They also suggest that chronic COC-induced I Na reduction may be attributed to a reduction in Ca 2þ signaling, which disrupts the physiological balance of phosphorylation and dephosphorylation of Na þ channels.Neuropsychopharmacology (

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“…Possible candidates for promoting memory-enhancing effects are those involved in downstream pathways activated by drugs of abuse (Nestler, 2001). Such drugs of abuse, including Meth, increase dopaminergic neurotransmission, which activates PKA and the phosphoprotein, dopamine-and cyclic AMP-regulated phosphoprotein (DARPP-32; also known as PPPR1RB), and this molecule in turn inhibits protein phosphatase-1 (Greengard et al, 1999;Lin et al, 2002;Svenningsson et al, 2005). Likely candidates involved in the cascade of events include protein kinase A (PKA), protein kinase C (PKC), and/or inhibition of phosphatase activity; the last two have been shown to be involved in boosting ITM into LTM in Lymnaea (Rosenegger et al, 2008).…”

Section: Effect Of Meth Pre-exposure On Ltm Formationmentioning

confidence: 99%

“…Likely candidates involved in the cascade of events include protein kinase A (PKA), protein kinase C (PKC), and/or inhibition of phosphatase activity; the last two have been shown to be involved in boosting ITM into LTM in Lymnaea (Rosenegger et al, 2008). Meth may inhibit the active process of forgetting via effects on protein phosphatase activity (Lin et al, 2002;Snyder et al, 2000). Given the relatively long period of time between Meth exposure and the first training session (24h), Meth may also influence the ability to alter synapse formation via factors such as the EGF-like peptide found in Lymnaea (Hamakawa et al, 1999;van Kesteren et al, 2008).…”

Section: Effect Of Meth Pre-exposure On Ltm Formationmentioning

confidence: 99%

Methamphetamine enhances memory of operantly conditioned respiratory behavior in the snail Lymnaea stagnalis

Kennedy

Houmes

Wyrick

et al. 2010

Journal of Experimental Biology

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SUMMARYAmphetamines have been used as cognitive enhancers to promote learning and memory. Amphetamines are also drugs of abuse that may promote the initiation of strong memories that ultimately lead to addiction. To understand how methamphetamine (Meth) may be augmenting learning and memory, we chose a relatively simple system, the pond snail, Lymnaea stagnalis. We studied the effects of Meth exposure on the long-term memory (LTM), extinction and reinstatement of operantly conditioned aerial respiratory behavior in Lymnaea. We first determined doses of Meth that would acutely alter respiratory behavior. Next, we measured the impact of training snails in Meth solution or water (control group) using a training procedure that produces LTM (>6h) in control conditions. Meth exposure impaired the expression of LTM 21h after two training sessions, but this appeared to be a context-dependent effect only. However, snails exposed to 3.3mmoll -1 Meth during training had a decreased rate of extinction of the operantly conditioned memory. We then tested whether this decreased ability of snails to extinguish memory was due to enhanced LTM or impaired extinction of that memory. Snails were operantly conditioned in water and exposed to Meth 16h after their last trial but 4-5h prior to extinction. Meth produced an increase rather than a decrease in extinction rate. Thus, Meth impaired extinction only when snails were exposed to Meth during training. Last, we tested the effect of Meth on the ability to form LTM using a single training procedure that is suboptimal for LTM formation. Control snails did not demonstrate LTM, as expected, but pre-exposure of snails to 3.3mmoll -1 Meth 24h prior to the single training session produced LTM 24h later, indicating that Meth pre-exposure primed snails for LTM formation. Taken together, our studies suggest that LTM is strengthened by Meth such that extinction training is less effective. Lymnaea provides a simple and useful model system to dissect the cellular and/or molecular mechanisms of how Meth may initiate the formation of stronger memories.

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Decreased calcineurin and increased phosphothreonine‐DARPP‐32 in the striatum of rats behaviorally sensitized to methamphetamine

Cited by 18 publications

References 35 publications

GABAB Receptor-Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

GABAB Receptor-Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

Repeated Cocaine Administration Decreases Calcineurin (PP2B) but Enhances DARPP-32 Modulation of Sodium Currents in Rat Nucleus Accumbens Neurons

Methamphetamine enhances memory of operantly conditioned respiratory behavior in the snail Lymnaea stagnalis

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